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Islet Amyloid Polypeptide (Amylin) Is Expressed in Sensory Neurons

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Islet Amyloid Polypeptide (Amylin) Is Expressed in Sensory Neurons The Journal of Neuroscience, November 1995, 75(11): 7625-7632 Islet Amyloid Polypeptide (Amylin) Is Expressed in Sensory Neurons Hindrik Mulder,’ Arnold Leckstriim,* Rolf Uddman,3 Eva Ekblad,’ Per Westermark: and Frank SundIet-’ ‘Department of Medical Cell Research, University of Lund, *Department of Pathology, University Hospital, LinkQping, and 3Department of Otolaryngology at Malm6 General Hospital, University of Lund, Sweden Islet amyloid polypeptide (IAPP) or amylin is a hormone predominantly expressed in insulin cells (Johnson et al., 1988), candidate predominantly expressed in insulin cells. A role where it is stored in the same secretory granules as insulin (Lu- for IAPP in the regulation of glucose homeostasis and the kinius et al., 1989). The physiological role of IAPP has not yet development of non-insulin-dependent diabetes mellitus been resolved. However, the data available suggest a role for has been proposed. IAPP is structurally related to the sen- IAPP in glucose homeostasis: IAPP constrains insulin-mediated sory neuropeptide calcitonin gene-related peptide. In the glycogenesis in skeletal muscle (Leighton and Cooper, 1988; present study, using in situ hybridization, immunocyto- Frontoni et al., 1991) and inhibits insulin secretion (Wang et al., chemistry, and immunochemistry, the expression of IAPP 1993; Fiirnsinn et al., 1994). in sensory neurons in the rat was investigated. IAPP was IAPP bears an approximately 50% structural homology with expressed in a population of small- to medium-sized nerve calcitonin gene-related peptide (CGRP) (Westermark et al., cell bodies in dorsal root ganglia from all levels and in the 1986; Cooper et al., 1987), which is widely expressed in the jugular-nodose and trigeminal ganglion; IAPP-expressing CNS and PNS, the sensory nervous system in particular (Sundler nerve cell bodies constituted a subpopulation of those ex- et al., 1985; Ishida-Yamamoto and Tohyama, 1989). The genes pressing calcitonin gene-related peptide. In addition, IAPP- for IAPP and CGRP are located on chromosomes 12 and 11, like immunoreactivity occurred in nerve cell bodies storing respectively, and are probably the result of a duplication of an substance P and pituitary adenylate cyclase-activating ancestral gene (Hoppener et al., 1984; Nishi et al., 1989). polypeptide. IAPP-immunoreactive nerve fibers were en- Against this background, it is tempting to speculate that IAPP countered in the dorsal horns of the spinal cord, and to a is also expressed in the nervous system. In fact, IAPP mRNA lesser extent in peripheral tissues receiving sensory inner- has been demonstrated in extracts from rat dorsal root ganglia vation; IAPP-immunoreactive fibers constituted a subpop- (Ferrier et al., 1989; Nicholl et al., 1992) and, recently, it was ulation of those containing calcitonin gene-related peptide shown that in the chicken IAPP is predominantly expressed in and/or substance P. The immunochemical determinations the brain (Fan et al., 1994). However, the cellular expression demonstrated a low level of IAPP-like immunoreactivity in and distribution of IAPP in the sensory nervous system are not the dorsal root ganglia and spinal cord, which chromato- known. Therefore, by use of in situ hybridization, immunocy- graphically coeluted with authentic rat IAPP. We conclude tochemistry, and immunochemistry, we have investigated the that IAPP is expressed in sensory neurons, thus being a expression of IAPP in sensory ganglia and its occurrence in the novel sensory neuropeptide. candidate for which a physi- spinal cord and neuronal elements of peripheral tissues in the ological role remains to be identified. rat. [Key words: islet amyloid polypeptide, amylin, calcitonin gene-related peptide, neuropeptides, sensory nervous sys- Materials and Methods tem, in situ hybridization, immunocytochemistry, radioim- Tissue. Adult female Sprague-Dawley rats (n = 10) were used; they munoassay (R/A)] were anesthetized by pentobarbitone and killed by exsanguination. Dor- sal root ganglia from the levels C, to L,, jugular-nodose, and trigeminal Islet amyloid polypeptide (IAPP), also designated amylin, is the ganglia were rapidly dissected. The following tissues were investigated main constituent of amyloid formed in insulinomas or in islets for the possible occurrence of IAPP-containing nerve fibers: nose skin, tongue, foot pad, airways, oesophagus, gastrointestinal tract, pancreas, from patients with non-insulin-dependent diabetes mellitus urinary bladder, uterus, and spinal cord (cervical, thoracic, and lumbar (Westermark et al., 1986; Cooper et al., 1987). The peptide is levels). In addition, dorsal root ganglia and spinal cord from newborn rats (day 0; n = 5) were excised. For in situ hybridization, the speci- mens were frozen on dry ice and stored at -80°C; for immunocyto- Received Apr. 17, 1995; revised July 21, 1995; accepted July 25, 1995. chemistry, the specimens were immersed overnight in 2% paraformal- This study was supported by the Swedish Medical Research Council (Project dehyde and 0.2% picric acid (buffered in 0.1 M phosphate, pH 7.2) 12X-4499 and 5941). The Swedish Diabetes Association, The Heart Lung, followed by repeated rinsing in sucrose-enriched (10%) buffer. The Albert Pahlsson, Wiberg and Crafoord Foundations, The Novo Nordisk Insulin specimens were frozen on dry ice and stored at -80°C until being cut Fund and the Faculties of Medicine, University of Lund and University of Linkoping. We gratefully thank Dr. Amy Percy, Mr. Mark Fineman, and Dr. on a cryostat (10 km). For immunochemistry (radioimmunoassay, RIA) Joy Koda (Amylin Pharmaceuticals Inc., San Diego, CA) for providing F 055. and reverse phase high-performance liquid chromatography (HPLC), 24 and data on antibodv characterization. pooled (n = 10) dorsal root ganglia and specimens from the spinal cord Correspondence should be addressed to Hindrik Mulder, M.D., Department were frozen on dry ice. of Medical Cell Research, University of Lund, Biskopsgatan 5, S-22362 Lund, In situ hybrid&ion. Two 30-mer oligodeoxyribonucleotide probes Sweden. complementary to nucleotides 80-109 and 215-244 in cDNA encoding Copyright 0 1995 Society for Neuroscience 0270.6474/95/157625-08$05.00/O rat IAPP were used (Leffert et al., 1989). These sequences were unique 7626 Mulder et al. - IAPP/Amylin in Sensory Neurons Table I. Details of antibodies used for immunocytochemistry Code Antigen Raised in Dilution Source F 055-24 Human IAPP l-10 Monoclonal 1:320 Amylin Pharmaceuticals Inc., San Diego, CA 8425 Rat a-CGRP Rabbit 1:640 Euro-Diagnostica, Malmo, Sweden SP I Substance P Rabbit I:160 Dr. P Emson, MRC Gruop, Cambridge, UK 9223 Nitric oxide synthase Rabbit I:1280 Euro-Diagnostica 88121-3 PACAP l-27 Rabbit 1:640 Dr. A. Arimura, Tulane University School of Medicine, New Orleans, LA N-SOM Somatostatin Rabbit I:800 Inc. Star Corp., Stillwater, MN 8416 Porcine galanin Rabbit 1:320 Euro-Diagnostica for rat IAPP mRNA (GenBank EMBL, 12/94). Also, a 30.mer oligo- Morphometry. The diameters of nerve cell bodies in dorsal root gan- probe complementary to nucleotides 3839-3868 in rat oi-CGRP cDNA glia labeled by the IAPP probes were determined. Using a calibrated was used (Amara et al., 1984). The probes were 3’.endtailed with “S- scale bar inserted into the eyepiece of the microscope, 100 consecutive dATP as previously described (Mulder et al., 1993). The protocol for nucleated nerve cell bodies from levels C, to L? were measured in in situ hybridization was adopted with modifications from Dagerlind et darkfield. Further, the percentage of IAPP probe-labeled nerve cell bod- al. (1992). Fresh frozen sections (10 km) were thaw mounted onto ies (847 counted) in dorsal root ganglia was determined in two to three chrome-alum-coated slides and stored overnight at -20°C. The slides sections from 12 ganglia from different levels (C, to L,). In addition, were rapidly warmed to room temperature and the hybridization solu- three to four consecutive sections of the two dorsal root ganglia from tion was applied to the sections. The hybridization buffer has previously levels C, to L, were processed for IAPP immunofluorescence. The num- been described (Mulder et al., 1993); the concentration of the IAPP and ber of IAPP-immunoreactive nerve cell bodies in each section was de- CGRP probes were 2.0 and I .O pmol/ml, respectively. The IAPP probes termined, and the frequency at each level calculated. Data on percentage were used separately or in a mix containing an equimolar amount of of IAPP probe-labeled cells and frequency of IAPP-immunoreactive the probes. Prior to hybridization, dithiothreitol was added to the hy- cells are given as mean -t SEM. bridization buffer at a final concentration of 0.2 M. Hybridization was Radioimmunoassay and reverse phase high-petformance liquid chro- carried out overnight in sealed moist chambers at 37°C. After hybrid- matography. The RIA has previously been described in detail (Christ- ization the coverslips were removed by immersion in 1 X saline sodium manson et al., 1993). Briefly, the assay is based on rabbit anti-human citrate (SSC; 0.15 M NaCl, 0.015 M sodium citrate) at room temperature. IAPP antiserum (Peninsula, Merseyside, UK) with labeled rat IAPP The sections were washed in 1 X SSC at 55°C (4X 15 min) and once (Amersham, Solna, Sweden) as tracer; the assay detects changes be- at room temperature (30 min). Finally, the sections were dehydrated and tween adjacent samples equivalent to 80 fmol/gm wet weight tissue. cleared in chloroform, after which they were air dried. For autoradiog- Before assay, dorsal root ganglia and specimens from spinal cord raphy, the slides were dipped in Ilford K-5 emulsion diluted 1: I with [weighing 10 mg (10 pooled ganglia) and 20-50 mg, respectively] were distilled water, air dried, and kept refrigerated at 4°C in light-sealed boiled in 0.5 M acetic acid (10 ml/g wet weight tissue or not less than boxes. After 2 and 4 weeks of exposure (CGRP and IAPP, respectively), 200 ~1); the extracts were assayed in duplicate dilutions equivalent to the autoradiographs were developed in Kodak D- 19 and counterstained 5, 15, and 25 pJtube.
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